Chemoinformatics analysis identifies cytotoxic compounds susceptible to chemoresistance mediated by glutathione and cystine/glutamate transport system xc-

Glutathione detoxification has been broadly implicated in resistance to chemotherapy. This study explores the relationship between chemical structure and GSH-mediated chemoresistance. System x(c)(-), the heterodimeric cystine/glutamate exchanger composed of SLC7A11 and SLC3A2, plays a role in maintaining cellular glutathione (GSH) levels. Previous results show that SLC7A11 expression negatively correlates with drug potency across the National Cancer Institute's 60 cell lines for compounds susceptible to GSH-mediated chemoresistance. The number of significant SLC7A11-drug correlations was much greater than those of other genes tested, suggesting that SLC7A11 plays a critical role. Approximately 15% of a curated set of 3045 compounds yielded significant negative SLC7A11 correlations. These compounds tend to contain structural features amenable to GSH reactivity, such as Mannich bases. In cell lines strongly expressing SLC7A11, the potency of selected compounds, was enhanced by inhibition of SLC7A11. This system provides a rapid screen for detecting susceptibility of anticancer drugs to GSH-mediated resistance.